Alzheimer's disease (AD) is the leading cause of dementia, and there is a pressing need to develop treatments to mitigate its enormous human and public health impact. Amyloid- (A) is a key pathogenic factor in AD, but its mechanisms of action are not well understood. In addition to damaging neurons and glia, A also impairs vital neurovascular mechanisms that regulate the cerebral blood supply, thus increasing the brain's susceptibility to hypoxic-ischemic injury. Vascular dysfunction may also compromise brain A clearance, promoting the retention of the peptide and its damaging effects. During the previous funding period we have established that A exerts its deleterious vascular effects by engaging the A-binding scavenger receptor CD36. CD36, in turn, leads to the production of reactive oxygen species (ROS) by activating Nox2. However, the cells expressing CD36 on which brain A acts on the abluminal side of cerebral blood vessels to increase Nox2-dependent ROS production remain unknown and their elucidation may suggest novel targets for AD therapy. Resident brain macrophages, mainly perivascular macrophages (PVM), reside along the A clearance pathway, express CD36 and Nox2, and are in close contact with the outer vessel wall. Therefore, PVM are uniquely positioned to contribute to vascular oxidative stress and neurovascular dysfunction induced by brain A. The central hypothesis of this application is that CD36 in PVM participates in the deleterious vascular effects of A and in the long-term consequences of A overproduction. We will test the following specific hypotheses: (1) PVM are the cells on which brain A acts to induce vascular oxidative stress and dysfunction; (2) CD36 in PVM is responsible for these actions of A, and (3) CD36 in PVM contributes to the long-term consequences of A overproduction, including cognitive deficits and perivascular A accumulation. Our studies will use state-of-the-art methods to investigate neurovascular regulation in mice. Pharmacological approaches and bone marrow chimeras will be used to investigate the specific role of CD36 in PVM in A-induced oxidative stress, neurovascular dysfunction, and cognitive deficits.